What doesn't kill you makes you stronger: Mitochondrial hormesis and sirtuin 3

Abstract

One of medicine's most unresolved mysteries is why reduced caloric intake and exercise slow aging and lower the risk for Alzheimer's disease (AD). Making progress towards this long-known phenomenon might resolve today's medical challenges. Mitochondria impact longevity not only by generating reactive oxygen species (ROS) but also by activating stress signals. Caloric restriction, fasting and exercise all cause mild metabolic and oxidative stress. Contrary to the popular belief, mild oxidative stress is not only harmless but even beneficial, endering the organism resistant against bigger insults. This adaptive response to mild stress, known as hormesis, might extend lifespan and fail in AD. Sirtuin 3 (SIRT3), a mitochondrial NAD + dependent protein eacetylase, is implicated in longevity. SIRT3 is upregulated by caloric restriction, fasting and exercise. Mild oxidative stress also increases SIRT3. In mitochondria, SIRT3 deacetylates and activates enzymes of the energy metabolism and antioxidant defenses. In addition, SIRT3 inhibits apoptosis by oxidative stress. Accordingly, SIRT3 might be indispensible for hormesis. Mitochondria undergo frequent fission and fusion cycles. This dynamic process safeguards organelle quality, energy production, and transport. Balanced mitochondrial fission and fusion is regulated by dynamin-related GTPases. Ab and excessive oxidative stress cause mitochondrial fragmentation by activation of fission and inhibition of fusion. Increasing fusion protects against Ab and oxidative stress neurotoxicity. We postulate that Ab might eradicate the SIRT3-mediated response, sensitizing neurons to mitochondrial fragmentation, bioenergetic failure, ROS overproduction and injury. We integrated biochemistry, cell biology, genetics and neuroscience with in vitro and in vivo systems. Mild oxidative stress stimulates mitochondrial fusion and increases SIRT3. By contrast, excess oxidative stress lowers SIRT3 and causes mitochondrial fragmentation and apoptosis. In addition, Ab decreases SIRT3, causing mitochondrial fragmentation. Furthermore, SIRT3 expression is reduced in AD mice. Consequently, SIRT3 substrates including mitochondrial fission/fusion GTPases are hyperacetylated. Fasting in SIRT3-null mice causes excessive oxidative stress, mitochondrial fragmentation, and hyperacetylation of mitochondrial fission/fusion GTPases. Reducing Ab-induced oxidative stress with N-acetyl-cysteine has restoresmitochondrial dynamics and the acetylation of fission/fusion GTPases. SIRT3 and mitochondrial dynamics might regulate hormesis. Enhancing SIRT3 activity might slow neuronal injury in AD.